THE NONPEPTIDE NK-1 RECEPTOR ANTAGONIST LY303870 INHIBITS NEUROGENIC DURAL INFLAMMATION IN GUINEA-PIGS

LY303870 is a competitive, high affinity NK-1 receptor antagonist. It was tested in the trigeminal stimulation-induced neurogenic dural infl ammation model of migraine. The neurogenic inflammation theory of migr aine pain proposes that substance P, acting through NK-1 receptors, ca uses dural inflammation which enhances migraine pain. LY303870 adminis tration potently inhibited neurogenic dural inflammation as measured b y plasma protein extravasation caused by electrical stimulation of the trigeminal ganglion in guinea pigs. It was active in this model when administered via intravenous, oral or inhalation routes. LY306155, the enantiomer of LY303870 with lower affinity for the NK-1 receptor, was much less potent than LY303870 in this model. LY303870, at oral doses of 1, 10 and 100 mu g/kg, produced a long, dose-dependent inhibition of dural inflammation, demonstrating a suitable duration of action for a potential use in acute migraine and migraine prophylaxis.